tbuckley/cabot-search huggingface dataset:
Therapeutic potential of exosome‐based personalized delivery platform in chronic inflammatory diseases
Authors: Chenglong Wang, Maochang Xu, Qingze Fan, Chunhong Li, Xiangyu Zhou
Journal: Asian Journal of Pharmaceutical Sciences (2022)

In the inflammatory microenvironment, there are numerous exosomes secreted by immune cells (Macrophages, neutrophils, dendritic cells), mesenchymal stem cells (MSCs) and platelets as intercellular communicators, which participate in the regulation of inflammation by modulating gene expression and releasing anti-inflammatory factors. Due to their good biocompatibility, accurate targeting, low toxicity and immunogenicity, these exosomes are able to selectively deliver therapeutic drugs to the site of inflammation through interactions between their surface-antibody or modified ligand with cell surface receptors. Therefore, the role of exosome-based biomimetic delivery strategies in inflammatory diseases has attracted increasing attention. Here we review current knowledge and techniques for exosome identification, isolation, modification and drug loading. More importantly, we highlight progress in using exosomes to treat chronic inflammatory diseases such as rheumatoid arthritis (RA), osteoarthritis (OA), atherosclerosis (AS), and inflammatory bowel disease (IBD). Finally, we also discuss their potential and challenges as anti-inflammatory drug carriers.
Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis
Authors: Susana Garcia-Recio, Toshinori Hinoue, Gregory L. Wheeler, Benjamin J. Kelly, Ana C. Garrido-Castro, Tomas Pascual, Aguirre A. De Cubas, Youli Xia, Brooke M. Felsheim, Marni B. McClure, Andrei Rajkovic, Ezgi Karaesmen, Markia A. Smith, Cheng Fan, Paula I. Gonzalez Ericsson, Melinda E. Sanders, Chad J. Creighton, Jay Bowen, Kristen Leraas, Robyn T. Burns, Sara Coppens, Amy Wheless, Salma Rezk, Amy L. Garrett, Joel S. Parker, Kelly K. Foy, Hui Shen, Ben H. Park, Ian Krop, Carey Anders, Julie Gastier-Foster, Mothaffar F. Rimawi, Rita Nanda, Nancy U. Lin, Claudine Isaacs, P. Kelly Marcom, Anna Maria Storniolo, Fergus J. Couch, Uma Chandran, Michael Davis, Jonathan Silverstein, Alexander Ropelewski, Minetta C. Liu, Susan G. Hilsenbeck, Larry Norton, Andrea L. Richardson, W. Fraser Symmans, Antonio C. Wolff, Nancy E. Davidson, Lisa A. Carey, Adrian V. Lee, Justin M. Balko, Katherine A. Hoadley, Peter W. Laird, Elaine R. Mardis, Tari A. King, Aguirre A. De Cubas, Charles M. Perou
Journal: Nature Cancer (2022)

Abstract The AURORA US Metastasis Project was established with the goal to identify molecular features associated with metastasis. We assayed 55 females with metastatic breast cancer (51 primary cancers and 102 metastases) by RNA sequencing, tumor/germline DNA exome and low-pass whole-genome sequencing and global DNA methylation microarrays. Expression subtype changes were observed in ~30% of samples and were coincident with DNA clonality shifts, especially involving HER2. Downregulation of estrogen receptor (ER)-mediated cell–cell adhesion genes through DNA methylation mechanisms was observed in metastases. Microenvironment differences varied according to tumor subtype; the ER + /luminal subtype had lower fibroblast and endothelial content, while triple-negative breast cancer/basal metastases showed a decrease in B and T cells. In 17% of metastases, DNA hypermethylation and/or focal deletions were identified near HLA-A and were associated with reduced expression and lower immune cell infiltrates, especially in brain and liver metastases. These findings could have implications for treating individuals with metastatic breast cancer with immune- and HER2-targeting therapies.
Retraction Note: Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway
Authors: Jia-Xing Zhang, Yi Xu, Ying Gao, Cui Chen, Zhou-San Zheng, Miao Yun, Hui-Wen Weng, Dan Xie, Sheng Ye
Journal: Molecular Cancer (2022)

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12943-017-0586-y.
Author Correction: Virtual exam for Parkinson’s disease enables frequent and reliable remote measurements of motor function
Authors: Maximilien Burq, Erin Rainaldi, King Chung Ho, Chen Chen, Bastiaan R. Bloem, Luc J. W. Evers, Rick C. Helmich, Lance Myers, William J. Marks, Ritu Kapur
Journal: npj Digital Medicine (2022)
Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer
Authors: Tizita Z. Zeleke, Qingfei Pan, Codruta Chiuzan, Maika Onishi, Yuxin Li, Haiyan Tan, Mariano J. Alvarez, Erin Honan, Min Yang, Pei Ling Chia, Partha Mukhopadhyay, Sean Kelly, Ruby Wu, Kathleen Fenn, Meghna S. Trivedi, Melissa Accordino, Katherine D. Crew, Dawn L. Hershman, Matthew Maurer, Simon Jones, Anthony High, Junmin Peng, Andrea Califano, Kevin Kalinsky, Jiyang Yu, Jose Silva
Journal: Nature Cancer (2022)
The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations
Authors: Anita Villani, Scott Davidson, Nisha Kanwar, Winnie W. Lo, Yisu Li, Sarah Cohen-Gogo, Fabio Fuligni, Lisa-Monique Edward, Nicholas Light, Mehdi Layeghifard, Ricardo Harripaul, Larissa Waldman, Bailey Gallinger, Federico Comitani, Ledia Brunga, Reid Hayes, Nathaniel D. Anderson, Arun K. Ramani, Kyoko E. Yuki, Sasha Blay, Brittney Johnstone, Cara Inglese, Rawan Hammad, Catherine Goudie, Andrew Shuen, Jonathan D. Wasserman, Rosemarie E. Venier, Marianne Eliou, Miranda Lorenti, Carol Ann Ryan, Michael Braga, Meagan Gloven-Brown, Jianan Han, Maria Montero, Famida Spatare, James A. Whitlock, Stephen W. Scherer, Kathy Chun, Martin J. Somerville, Cynthia Hawkins, Mohamed Abdelhaleem, Vijay Ramaswamy, Gino R. Somers, Lianna Kyriakopoulou, Johann Hitzler, Mary Shago, Daniel A. Morgenstern, Uri Tabori, Stephen Meyn, Meredith S. Irwin, David Malkin, Adam Shlien
Journal: Nature Cancer (2022)

We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.
Polymeric ligands comprising sulfur-containing amino acids for targeting tumor-associated amino acid transporters
Authors: Haochen Guo, Wen Xu, Takahiro Nomoto, Kaito Kanamori, Yan Ming Voon, Yuto Honda, Naoki Yamada, Hiroyasu Takemoto, Makoto Matsui, Nobuhiro Nishiyama
Journal: Biomaterials (2022)
Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer
Authors: Pat Gulhati, Aislyn Schalck, Shan Jiang, Xiaoying Shang, Chang-Jiun Wu, Pingping Hou, Sharia Hernandez Ruiz, Luisa Solis Soto, Edwin Parra, Haoqiang Ying, Jincheng Han, Prasenjit Dey, Jun Li, Pingna Deng, Emi Sei, Dean Y. Maeda, John A. Zebala, Denise J. Spring, Michael Kim, Huamin Wang, Anirban Maitra, Dirk Moore, Karen Clise-Dwyer, Y. Alan Wang, Nicholas E. Navin, Ronald A. DePinho
Journal: Nature Cancer (2022)
Retraction Notice to: Selective Targeting of Checkpoint Kinase 1 in Tumor Cells with a Novel Potent Oncolytic Adenovirus
Authors: Qinglei Gao, Jianfeng Zhou, Xiaoyuan Huang, Gang Chen, Fei Ye, Yunping Lu, Kanyan Li, Liang Zhuang, Mei Huang, Gang Xu, Shxuan Wang, Ding Ma
Journal: Molecular Therapy (2022)
Interferon Biology and LAG-3 Shedding in PD-(L)1 plus LAG-3 Immunotherapy
Authors: Lilit Karapetyan, Jason J. Luke
Journal: Clinical Cancer Research (2022)

Targeting coinhibitory receptors on dysfunctional T cells may improve response to anti-PD-(L)1 in the IFNγ associated T-cell-inflamed tumor microenvironment. The bispecific lymphocyte activation gene 3 (LAG-3) and PD-L1 blocking antibody FS118, potentially through LAG-3 shedding, represents a promising strategy to improve immune checkpoint blockade. Soluble LAG-3 is an intriguing biomarker for LAG-3 drug activity. See related article by Yap et al., p. 888.
Targeting immune checkpoints: how to use natural killer cells for fighting against solid tumors
Authors: Farhoodeh Ghaedrahmati, Nafiseh Esmaeil, Maryam Abbaspour
Journal: Cancer Communications (2022)

Abstract Natural killer (NK) cells are unique innate immune cells that mediate anti‐viral and anti‐tumor responses. Thus, they might hold great potential for cancer immunotherapy. NK cell adoptive immunotherapy in humans has shown modest efficacy. In particular, it has failed to demonstrate therapeutic efficiency in the treatment of solid tumors, possibly due in part to the immunosuppressive tumor microenvironment (TME), which reduces NK cell immunotherapy's efficiencies. It is known that immune checkpoints play a prominent role in creating an immunosuppressive TME, leading to NK cell exhaustion and tumor immune escape. Therefore, NK cells must be reversed from their dysfunctional status and increased in their effector roles in order to improve the efficiency of cancer immunotherapy. Blockade of immune checkpoints can not only rescue NK cells from exhaustion but also augment their robust anti‐tumor activity. In this review, we discussed immune checkpoint blockade strategies with a focus on chimeric antigen receptor (CAR)‐NK cells to redirect NK cells to cancer cells in the treatment of solid tumors.
Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology
Authors: Ankit Verma, Anna Shteinfer-Kuzmine, Nikita Kamenetsky, Srinivas Pittala, Avijit Paul, Edna Nahon Crystal, Alberto Ouro, Vered Chalifa-Caspi, Swaroop Kumar Pandey, Alon Monsonego, Noga Vardi, Shira Knafo, Varda Shoshan-Barmatz
Journal: Translational Neurodegeneration (2022)

Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca2+ homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction.To address the multiple pathways involved in AD, neuronal cultures and a 5 × FAD mouse model of AD were treated with VBIT-4. We addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting, immunofluorescence, q-RT-PCR, 3-D structural analysis and several behavioral tests.In neuronal cultures, amyloid-beta (Aβ)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by VBIT-4. Using an AD-like 5 × FAD mouse model, we showed that VDAC1 was overexpressed in neurons surrounding Aβ plaques, but not in astrocytes and microglia, and this was associated with neuronal cell death. VBIT-4 prevented the associated pathophysiological changes including neuronal cell death, neuroinflammation, and neuro-metabolic dysfunctions. VBIT-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective phenotype. Moreover, VBIT-4 prevented cognitive decline in the 5 × FAD mice as evaluated using several behavioral assessments of cognitive function. Interestingly, VBIT-4 protected against AD pathology, with no significant change in phosphorylated Tau and only a slight decrease in Aβ-plaque load.The study suggests that mitochondrial dysfunction with its gatekeeper VDAC1 is a promising target for AD therapeutic intervention, and VBIT-4 is a promising drug candidate for AD treatment.
Endothelial PTP4A1 mitigates vascular inflammation via USF1/A20 axis-mediated NF-κB inactivation
Authors: Min Ji Cho, Dong Gwang Lee, Jeong Woong Lee, Byungtae Hwang, Sung-Jin Yoon, Seon-Jin Lee, Young-Jun Park, Seung-Ho Park, Hee Gu Lee, Yong-Hoon Kim, Chul-Ho Lee, Jangwook Lee, Nam-Kyung Lee, Tae-Su Han, Hyun-Soo Cho, Jeong Hee Moon, Ga Seul Lee, Kwang-Hee Bae, Geum-Sook Hwang, Sang-Hak Lee, Sang J Chung, Sungbo Shim, Jaehyung Cho, Goo Taeg Oh, Young-Guen Kwon, Jong-Gil Park, Jeong-Ki Min
Journal: Cardiovascular Research (2022)

The nuclear factor-κB (NF-κB) signalling pathway plays a critical role in the pathogenesis of multiple vascular diseases. However, in endothelial cells (ECs), the molecular mechanisms responsible for the negative regulation of the NF-κB pathway are poorly understood. In this study, we investigated a novel role for protein tyrosine phosphatase type IVA1 (PTP4A1) in NF-κB signalling in ECs.In human tissues, human umbilical artery ECs, and mouse models for loss of function and gain of function of PTP4A1, we conducted histological analysis, immunostaining, laser-captured microdissection assay, lentiviral infection, small interfering RNA transfection, quantitative real-time PCR and reverse transcription-PCR, as well as luciferase reporter gene and chromatin immunoprecipitation assays. Short hairpin RNA-mediated knockdown of PTP4A1 and overexpression of PTP4A1 in ECs indicated that PTP4A1 is critical for inhibiting the expression of cell adhesion molecules (CAMs). PTP4A1 increased the transcriptional activity of upstream stimulatory factor 1 (USF1) by dephosphorylating its S309 residue and subsequently inducing the transcription of tumour necrosis factor-alpha-induced protein 3 (TNFAIP3/A20) and the inhibition of NF-κB activity. Studies on Ptp4a1 knockout or transgenic mice demonstrated that PTP4A1 potently regulates the interleukin 1β-induced expression of CAMs in vivo. In addition, we verified that PTP4A1 deficiency in apolipoprotein E knockout mice exacerbated high-fat high-cholesterol diet-induced atherogenesis with upregulated expression of CAMs.Our data indicate that PTP4A1 is a novel negative regulator of vascular inflammation by inducing USF1/A20 axis-mediated NF-κB inactivation. Therefore, the expression and/or activation of PTP4A1 in ECs might be useful for the treatment of vascular inflammatory diseases.
Long-term Small Population Size, Deleterious Variation, and Altitude Adaptation in the Ethiopian Wolf, a Severely Endangered Canid
Authors: Jazlyn A Mooney, Clare D Marsden, Abigail Yohannes, Robert K Wayne, Kirk E Lohmueller
Journal: Molecular Biology and Evolution (2022)

Abstract Ethiopian wolves, a canid species endemic to the Ethiopian Highlands, have been steadily declining in numbers for decades. Currently, out of 35 extant species, it is now one of the world's most endangered canids. Most conservation efforts have focused on preventing disease, monitoring movements and behavior, and assessing the geographic ranges of sub-populations. Here, we add an essential layer by determining the Ethiopian wolf's demographic and evolutionary history using high-coverage (∼40×) whole-genome sequencing from 10 Ethiopian wolves from the Bale Mountains. We observe exceptionally low diversity and enrichment of weakly deleterious variants in the Ethiopian wolves in comparison with two North American gray wolf populations and four dog breeds. These patterns are consequences of long-term small population size, rather than recent inbreeding. We infer the demographic history of the Ethiopian wolf and find it to be concordant with historic records and previous genetic analyses, suggesting Ethiopian wolves experienced a series of both ancient and recent bottlenecks, resulting in a census population size of fewer than 500 individuals and an estimated effective population size of approximately 100 individuals. Additionally, long-term small population size may have limited the accumulation of strongly deleterious recessive mutations. Finally, as the Ethiopian wolves have inhabited high-altitude areas for thousands of years, we searched for evidence of high-altitude adaptation, finding evidence of positive selection at a transcription factor in a hypoxia-response pathway [CREB-binding protein (CREBBP)]. Our findings are pertinent to continuing conservation efforts and understanding how demography influences the persistence of deleterious variation in small populations.
Multimodal Locomotion and Cargo Transportation of Magnetically Actuated Quadruped Soft Microrobots
Authors: Chenyang Huang, Zhengyu Lai, Xinyu Wu, Tiantian Xu
Journal: Cyborg and Bionic Systems (2022)

Untethered microrobots have attracted extensive attention due to their potential for biomedical applications and micromanipulation at the small scale. Soft microrobots are of great research importance because of their highly deformable ability to achieve not only multiple locomotion mechanisms but also minimal invasion to the environment. However, the existing microrobots are still limited in their ability to locomote and cross obstacles in unstructured environments compared to conventional legged robots. Nature provides much inspiration for developing miniature robots. Here, we propose a bionic quadruped soft thin-film microrobot with a nonmagnetic soft body and 4 magnetic flexible legs. The quadruped soft microrobot can achieve multiple controllable locomotion modes in the external magnetic field. The experiment demonstrated the robot's excellent obstacle-crossing ability by walking on the surface with steps and moving in the bottom of a stomach model with gullies. In particular, by controlling the conical angle of the external conical magnetic field, microbeads gripping, transportation, and release of the microrobot were demonstrated. In the future, the quadruped microrobot with excellent obstacle-crossing and gripping capabilities will be relevant for biomedical applications and micromanipulation.
A one-year genomic investigation of Escherichia coli epidemiology and nosocomial spread at a large US healthcare network
Authors: Emma G. Mills, Melissa J. Martin, Ting L. Luo, Ana C. Ong, Rosslyn Maybank, Brendan W. Corey, Casey Harless, Lan N. Preston, Joshua A. Rosado-Mendez, Scott B. Preston, Yoon I. Kwak, Michael G. Backlund, Jason W. Bennett, Patrick T. Mc Gann, Francois Lebreton
Journal: Genome Medicine (2022)

Extra-intestinal pathogenic Escherichia coli (ExPEC) are a leading cause of bloodstream and urinary tract infections worldwide. Over the last two decades, increased rates of antibiotic resistance in E. coli have been reported, further complicating treatment. Worryingly, specific lineages expressing extended-spectrum β-lactamases (ESBLs) and fluoroquinolone resistance have proliferated and are now considered a serious threat. Obtaining contemporary information on the epidemiology and prevalence of these circulating lineages is critical for containing their spread globally and within the clinic.Whole-genome sequencing (WGS), phylogenetic analysis, and antibiotic susceptibility testing were performed for a complete set of 2075 E. coli clinical isolates collected from 1776 patients at a large tertiary healthcare network in the USA between October 2019 and September 2020.The isolates represented two main phylogenetic groups, B2 and D, with six lineages accounting for 53% of strains: ST-69, ST-73, ST-95, ST-131, ST-127, and ST-1193. Twenty-seven percent of the primary isolates were multidrug resistant (MDR) and 5% carried an ESBL gene. Importantly, 74% of the ESBL-E.coli were co-resistant to fluoroquinolones and mostly belonged to pandemic ST-131 and emerging ST-1193. SNP-based detection of possible outbreaks identified 95 potential transmission clusters totaling 258 isolates (12% of the whole population) from ≥ 2 patients. While the proportion of MDR isolates was enriched in the set of putative transmission isolates compared to sporadic infections (35 vs 27%, p = 0.007), a large fraction (61%) of the predicted outbreaks (including the largest cluster grouping isolates from 12 patients) were caused by the transmission of non-MDR clones.By coupling in-depth genomic characterization with a complete sampling of clinical isolates for a full year, this study provides a rare and contemporary survey on the epidemiology and spread of E. coli in a large US healthcare network. While surveillance and infection control efforts often focus on ESBL and MDR lineages, our findings reveal that non-MDR isolates represent a large burden of infections, including those of predicted nosocomial origins. This increased awareness is key for implementing effective WGS-based surveillance as a routine technology for infection control.
lncRNA ZNRD1-AS1 promotes malignant lung cell proliferation, migration, and angiogenesis via the miR-942/TNS1 axis and is positively regulated by the m6A reader YTHDC2
Authors: Jin Wang, Lirong Tan, Xueting Yu, Xiyuan Cao, Beibei Jia, Rui Chen, Jianxiang Li
Journal: Molecular Cancer (2022)

Abstract Rationale Lung cancer is the most prevalent form of cancer and has a high mortality rate, making it a global public health concern. The N 6 -methyladenosine (m 6 A) modification is a highly dynamic and reversible process that is involved in a variety of essential biological processes. Using in vitro, in vivo, and multi-omics bioinformatics, the present study aims to determine the function and regulatory mechanisms of the long non-coding (lnc)RNA zinc ribbon domain-containing 1-antisense 1 (ZNRD1-AS1). Methods The RNAs that were bound to the m 6 A ‘reader’ were identified using YTH domain-containing 2 (YTHDC2) RNA immunoprecipitation (RIP)-sequencing. Utilizing methylated RIP PCR/quantitative PCR, pull-down, and RNA stability assays, m 6 A modification and ZNRD1-AS1 regulation were analyzed. Using bioinformatics, the expression levels and clinical significance of ZNRD1-AS1 in lung cancer were evaluated. Using fluorescent in situ hybridization and quantitative PCR assays, the subcellular location of ZNRD1-AS1 was determined. Using cell migration, proliferation, and angiogenesis assays, the biological function of ZNRD1-AS1 in lung cancer was determined. In addition, the tumor suppressor effect of ZNRD1-AS1 in vivo was validated using a xenograft animal model. Through bioinformatics analysis and in vitro assays, the downstream microRNAs (miRs) and competing endogenous RNAs were also predicted and validated. Results This study provided evidence that m 6 A modification mediates YTHDC2-mediated downregulation of ZNRD1-AS1 in lung cancer and cigarette smoke-exposed cells. Low levels of ZNRD1-AS1 expression were linked to adverse clinicopathological characteristics, immune infiltration, and prognosis. ZNRD1-AS1 overexpression was shown to suppress lung cancer cell proliferation, migration, and angiogenesis in vitro and in vivo , and to reduce tumor growth in nude mice. ZNRD1-AS1 expression was shown to be controlled by treatment of cells with either the methylation inhibitor 3-Deazaadenosine or the demethylation inhibitor Meclofenamic. Furthermore, the miR-942/tensin 1 (TNS1) axis was demonstrated to be the downstream regulatory signaling pathway of ZNRD1-AS1. Conclusions ZNRD1-AS1 serves an important function and has clinical relevance in lung cancer. In addition, the findings suggested that m 6 A modification could mediate the regulation of the ZNRD1-AS1/miR-942/TNS1 axis via the m 6 A reader YTHDC2. Graphical Abstract